Sample characteristics (n = 9,385).

Background
Physical activity (PA) is associated with a lower risk of cognitive decline and all-cause dementia in later life. Pathways underpinning this association are unclear but may involve either mediation and/or moderation by cardiorespiratory fitness (CRF).
Methods
Data on PA frequency (exposure) at 42y, non-exercise testing CRF (NETCRF, mediator/moderator) at 45y and overall cognitive function (outcome) at 50y were obtained from 9,385 participants (50.8% female) in the 1958 British birth cohort study. We used a four-way decomposition approach to examine the relative contributions of mediation and moderation by NETCRF on the association between PA frequency at 42y and overall cognitive function at 50y.
Results
In males, the estimated overall effect of 42y PA ≥once per week (vs. ) was a 0.08 (95% confidence interval: 0.04,0.13) higher overall cognitive function z-score at 50y. The estimated controlled direct effect was similar (0.08 (0.03, 0.12)). Thus, the proportion of the estimated effect via mediation or moderation by NETCRF was small (~3%), with confidence intervals straddling the null. In females, there was no estimated overall effect of PA frequency on overall cognitive function.
Conclusion
We present the first evidence from a four-way decomposition analysis of the potential contribution that CRF plays in the relationship between mid-life PA frequency and subsequent cognitive function. Our lack of evidence in support of CRF mediating or moderating the PA frequency―cognitive function association suggests that other pathways underpin this association.